In a staff report posted on FDA’s website, the agency took issue with Novartis’ reliance on one clinical trial to assess serelaxin’s effect on dyspnea rather than at least two, or a single trial with data for two or more studies. And while the single trial focused on how serelaxin could reduce labored breathing, FDA staffers Melanie Blank and Tzu-Yun McDowell called that “an exploratory finding” that did not address the AHF indication of the experimental drug, which Novartis plans to market under the name Reasanz.

“We recommend that serelaxin not be approved at this time because there is insufficient evidence to support the proposed indication: to improve the symptoms of acute heart failure through reduction of the rate of worsening of heart failure," Blank and McDowell concluded. They also faulted the company for a vague definition of worsening heart failure since it relied on the judgments of trial investigators.

Novartis responded to the staff report with a statement, furnished to GEN and stating its view that serelaxin was effective against AHF.

“Novartis believes that the evidence supporting RLX030 demonstrates a clinically significant beneficial effect in patients with AHF, with an overall favorable benefit-risk profile. Novartis looks forward to having an open dialogue about the RLX030 program with the Committee on March 27,” the company said.

“Each year more than 1 million people in the US are hospitalized for AHF, with around 22% of them likely to die within the year. New treatments are needed to treat this life-threatening condition,” Novartis added.

Serelaxin is a relaxin receptor agonist designed to relax the blood vessels, reduce fluid buildup and protect the heart and vital organs from damage wrought by an AHF episode.

Novartis has trumpeted results from its Phase III RELAX-AHF study, in which patients who received serelaxin had a 37% reduction in mortality at six months after an AHF episode compared to those who received conventional treatment. In September, Novartis started recruiting the first of more than 6,000 patients expected to participate in its second phase III study RELAX-AHF-2, with the goal of replicating the key findings of RELAX-AHF. Cardiovascular mortality will be RELAX-AHF-2’s primary endpoint.

FDA is set to decide on serelaxin by May 17. Novartis is counting on strong sales from serelaxin and other candidates to recoup patent-cliff losses for Diovan and cancer drug Gleevec.

The FDA staff report emerged some two months after a key advisory panel to the European Commission—the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP)—recommended against commission approval of serelaxin. CHMP said Novartis’ study results did not demonstrate a benefit for short-term relief of dyspnoea over up to 24 hours—and while acknowledging that some benefit was shown over five days, the panel said the clinical relevance of that finding was unclear.

Novartis responded to that setback by saying it would submit a new filing package, including new data analyses, in order to obtain conditional approval later this year, then submit a revised marketing approval application to the EMA.

In their review, Blank and McDowell also took issue with Novartis assigning to patients who died or experienced worsening heart failure the worst reported score (zero) from the time of occurrence of the event. FDA questioned whether the zero value may have overly influenced the results and that the primary endpoint might not have been achieved if a value other than zero had been assigned to patients who died or had worsening heart failure during the first 5 days.

Novartis sought to address FDA through an addendum to its briefing document for the panel in which it said its approach was consistent with that used in trials of new drugs in AHF carried out during the past decade. The company also submitted additional analyses showing that achievement of success on the VAS AUC primary endpoint in the RELAX-AHF trial did not depend on the assignment of an arbitrary numerical value to patients with an unfavorable clinical course.

“If the clinical course of patients in the trial was characterized and ranked only according to clinical judgment, a favorable effect of serelaxin was consistently identified, and the strength of evidence for this effect was very similar to the protocol-specified analytical approach,” Novartis stated.